Our long term goal is to develop an orally effective, non-toxic alternative and complimentary medicine (CAM) modality from Oriental herbs for prostate cancer (PCa) chemoprevention. We have found that the ethanol extract of Ka-mi-kae-kyuk-tang (KMKKT) consisting of 10 herbs (i) has strong anti-angiogenesis activity;(ii) inhibits the in vivo growth of human PC-3 androgen-independent PCa xenografts in nude mice;(iii) inhibits the in vivo growth of mouse Lewis lung carcinoma allograft;and (iv) inhibits colon cancer-liver metastasis in the mice. And importantly, the above effects of KMKKT were observed without adverse effects on body weight at the doses tested, supporting its excellent safety for long-term use. Given that carcinogenesis is a multi-stage process requiring many genetic and epigenetic alterations, effective preventive measures must selectively target multiple molecular targets and cellular processes important for cancer initiation, promotion, progression and metastasis. We hypothesize that (a) KMKKT will be a safe and effective CAM chemopreventive modality against primary prostate carcinogenesis through anti- angiogenic, cell cycle arrest and pro-apoptotic and anti-metastasis actions;and (b) the herb(s) responsible for the anti-angiogenesis and anti-metastasis activity can be identified to recapitulate this formula with a minimal number of herbs. Our specific aim 1 is to evaluate the chemopreventive efficacy of orally-administered KMKKT against the transgenic adenocarcinoma mouse prostate (TRAMP) model of primary prostate carcinogenesis and metastasis (Lu lab). We will compare the effect of orally-administered KMKKT vs. i.p. injection of KMKKT on genito-urinary (GU) tract weight, dorsolateral prostate (DLP) weight, ventral prostate (VP) and lesion progression in these respective lobes (Year 1) and then we will establish the impact of orally- administered KMKKT given at different stages of prostate lesion development on the long term survival of the TRAMP mice (Year 1-2). Aim 2 is to determine the PCa-relevant anti-angiogenesis and anti-metastasis activities of orally-administered KMKKT and identify active herbs for each activity through a single-herb deletion approached combined with individual herbal evaluation (Kim Lab). Positive chemopreventive efficacy without toxicity with the orally-administered KMKKT cocktail in Aim 1 will be a great impetus for its continued preclinical development to pave the way for planning human translational studies. Successful accomplishment of Aim 2 will enable us to determine, in the future, whether the chemopreventive action of the full formula can be recapitulated by a minimal number of herbs. The identified herbs will be excellent starting points to identify active chemicals for better QC/QA of the herbal CAM products as well as for further pharmacological R&D. PUBLIC HEALTH RELEVANCE: Prostate cancer (PCa) is the No. 2 cause of cancer death of men in the US. In spite of the advances in early detection and treatments, there is no cure for the late stage and metastatic disease. Chemoprevention has become recognized as a plausible and cost-effective alternative approach to reduce the morbidity and mortality of PCa. However, due to the complex nature of carcinogenesis, main stream single agent/target-based research has not led to the development of any effective chemopreventive modality for PCa so far. This R21 application specifically focuses on testing an Oriental herbal formula with demonstrable multiple targeting anti- cancer activities to support a paradigm shift to achieve that goal.